Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates

Definitions

• the present disclosure relates to the field of drug delivery, and more particularly to the use of an enhancer to enhance the permeation of a pharmacologically active agent through human or animal skin.
• Phosphodiesterase is an enzyme found in various tissues.
• the interest in PDEs as molecular targets of drug action has grown with the development of isozyme-selective PDE inhibitors that offer potent inhibition of selected isozymes without the side-effects attributed to nonselective inhibitors.
• Sildenafil, vardenafil and tadalafil are inhibitors of cGMP-specific phosphodiesterase type 5 (PDE-5).
• PDE-5 inhibitors are used to treat primary pulmonary hypertension (PPH), which is a disease in which blood vessels in the lungs become abnormally narrow; and erectile dysfunction.
• PPH primary pulmonary hypertension
• ED erectile dysfunction
• Viagra containing sildenafil
• Levitra containing vardenafil
• Glaxo-Smith-Kline-Beecham/Schering Plough containing tadalafil
• oral delivery is a convenient and non-invasive way of delivering a pharmacologically active compound, yet it has its own disadvantages. For example, it is slow acting, for the drug would have to go through the gastrointestinal system of the recipient before it can reach the intended target site such as penis for ED treatment. Further, it is more likely to cause a number of side-effects, for the drug will be circulated systematically instead of exerting its function locally.
• Transdermal delivery is a feasible solution to the above-identified disadvantages of oral formulation of PDE-5 inhibitors.
• Various substances are known to enhance the ability of drugs and agents to diffuse through the skin and other tissues.
• the more popular approach has been the employment of surface active agents.
• surface active agents enhance the permeability by actually damaging the barrier tissue. Only slight to moderate enhancement of penetration is effected with the prior art surface active agents.
• Another approach is to use certain organic solvents, such as dimethylsulfoxide (DMSO), dimethyl formamide (DMF) or ⁇ , ⁇ -dimethylacetamide, to enhance the penetration of active substances through stratum corneum.
• DMSO dimethylsulfoxide
• DMF dimethyl formamide
• ⁇ , ⁇ -dimethylacetamide ⁇ , ⁇ -dimethylacetamide
• this invention identifies several compounds that may enhance transdermal delivery of PDE-5 inhibitors, hence are useful for the development of an improved medicament for treating conditions or diseases mediated by PDE-5.
• the present disclosure is based on the finding that certain agent(s) is effective as an enhancer to promote transdermal delivery of a PDE-5 inhibitor, hence is useful as an agent or an adjuvant for developing a topical medicament for treating conditions or diseases mediated by PDE-5 such as erectile dysfunction or primary pulmonary hypertension. [0010] Accordingly, it is therefore an object of the present disclosure to provide an improved transdermal pharmaceutical composition with an enhanced transdermal absorption rate of a PDE-5 inhibitor.
• the improved composition includes a phosphodiesterase type-5 (PDE-5) inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient; and the improvement of the composition lies in having an enhancer of this invention, wherein the PDE-5 inhibitor and the enhancer are present in a ratio from about 20:1 to 2:1 in the improved composition of this invention. In one preferred example, the PDE-5 and the enhancer are present in a ratio of about 5:1 in the improved transdermal pharmaceutical composition.
• PDE-5 inhibitor and the enhancer are present in a ratio of about 5:1 in the improved transdermal pharmaceutical composition.
• the enhancer is selected from the group consisting of cocamidopropyl betaine, sodium lauroamphoacetate, quaternium-60, isostearamidopropyl morpholine lactate, dipropylene glycol and a combination thereof.
• the enhancer is cocamidopropyl betaine.
• the enhancer is a mixture of cocamidopropyl betaine and sodium lauroamphoacetate.
• the enhancer is a mixture of cocamidopropyl betaine, sodium lauroamphoacetate, and quaternium-60.
• the enhancer is a mixture of cocamidopropyl betaine, sodium lauroamphoacetate, quaternium-60, isostearamidopropyl morpholine lactate, and dipropylene glycol.
• the PDE-5 inhibitor is any of sildenafil, tadalafr or vardenafil. In one preferred example, the PDE-5 inhibitor is vardenafil, which is not in crystalline state.
• the improved pharmaceutical composition may be formulated into the form of a solution, a paste, a lotion, a cream, a gel, or a patch.
• improved pharmaceutical composition is a gel.
• the improved pharmaceutical composition is a skin patch.
• the present disclosure provides a method for enhancing transdermal delivery of a PDE-5 inhibitor in a subject.
• the method includes steps of administering to the subject the improved pharmaceutical composition of the present disclosure, which includes a PDE-5 inhibitor or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, and an enhancer of the present invention; wherein the PDE-5 inhibitor and the enhancer are present in a ratio from about 20:1 to 2:1 in the improved composition.
• the PDE-5 and the enhancer are administered in a ratio of about 5:1.
• the enhancer of the present invention is any of cocamidopropyl betaine, sodium lauroamphoacetate, quaternium-60, isostearamidopropyl morpholine lactate, dipropylene glycol or a combination thereof.
• the enhancer is cocamidopropyl betaine.
• the enhancer is a mixture of cocamidopropyl betaine and sodium lauroamphoacetate.
• the enhancer is a mixture of cocamidopropyl betaine, sodium lauroamphoacetate and quaternium-60.
• the enhancer is a mixture of cocamidopropyl betaine, sodium lauroamphoacetate, quaternium-60, isostearamidopropyl morpholine lactate, and dipropylene glycol.
• the PDE-5 inhibitor is any of sildenafil, tadalafi or vardenafil. In one preferred example, the PDE-5 inhibitor is vardenafil, which is not in crystalline state.
• the improved method and/or pharmaceutical composition of the present disclosure can attain the same therapeutic benefits to the recipient thereof at a reduced level of PDE-5 inhibitor.
• FIG 1 illustrates the effects of formulations of Example 2.1 on in vitro transdermal delivery of vardenafil in accordance with one embodiment of the present disclosure
• FIG 2 illustrates the effects of the formulations of Example 2.1 and the skin patch of Example 2.2 on in vivo transdermal delivery of vardenafil in accordance with one embodiment of the present disclosure.
• the term “enhancer” is defined as a substance that, when added to the pharmaceutical composition, enhances the absorption kinetics, hence the bioavailability of a pharmacologically active agent, i.e., the PDE-5 inhibitor, while having few or none of direct therapeutically effects when given by itself.
• transdermal delivery refers to delivery by passage of a compound or drug through the skin and into the bloodstream.
• Enhanced delivery "enhanced permeability”, “enhanced permeation”, or “enhanced absorption” are used interchangeably herein to represent an increase in the permeability of skin to a pharmacologically active agent, i.e., so as to increase the rate at which the drug (e.g., the PDE-5 inhibitor) permeates through the skin and enters the bloodstream.
• the enhanced permeation effected through the use of the improved composition of the present invention can be observed by measuring the rate of diffusion of a drug through animal or human skin using a diffusion cell apparatus as described in the Examples herein.
• a "pharmaceutically acceptable” component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
• an effective amount refers to an amount effective, at dosages, and for periods of time necessary, to achieve the desired therapeutically desired results with respect to the treatment of diseases or conditions mediated by PDE-5, such as erectile dysfunction or primary pulmonary hypertension.
• the therapeutically effective amount of the' PDE-5 in lBitor will vaTy from subject to subject not only for the particular PDE-5 inhibitor selected, the route of administration, and the ability of the PDE-5 inhibitor (alone or in combination with one or more PDE-5 inhibitor or other drugs) to elicit a desired response in the subject, but also factors such as state or severity of the condition to be alleviated, age, weight of the subject, the state of being of the subject, and the severity of the condition being treated, concurrent medication or special diets then being followed by the subject, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician. Dosage regimens may be adjusted to provide the improved therapeutic response. An effective amount is also one in which any toxic or detrimental effects of the compound or composition are outweighed by the therapeutically beneficial effects.
• the PDE-5 inhibitor is administered at a dosage and for a time such that the severity of the symptoms is decreased.
• subject refers to any animal (e.g., a mammal), including, but are not limited to humans, non-human primates, which is to be subjected under the treatment of this invention.
• patient and “subject” are used interchangeably herein in reference to a human subject.
• excipient means any inert substance (such as a powder or liquid) that forms a vehicle/carrier for the PDE-5 inhibitor and/or enhancer.
• the excipient is generally safe, non-toxic, and in a broad sense, may also include any known substance in the pharmaceutical industry useful for preparing pharmaceutical compositions such as, fillers, diluents, agglutinants, binders, lubricating agents, glidants, stabilizer, colorants, wetting agents, disintegrants, and etc.
• the practices of this invention are hereinafter described in detail with respect to a method and a pharmaceutical composition that improves the transdermal delivery effects, and, thus, enhances the bioavailability of a PDE-5 inhibitor in a subject.
• the improved transdermal pharmaceutical composition comprises, a phosphodiesterase type-5 (PDE-5) inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the improvement comprises, an enhancer selected from the group consisting of cocamidopropyl betaine, sodium lauroamphoacetate, quaternium-60, isostearamidopropyl morpholine lactate, dipropylene glycol and a combination thereof; wherein the PDE-5 inhibitor and the enhancer are present in a ratio from about 20:1 to 2:1 in the improved transdermal pharmaceutical composition
• the PDE-5 inhibitors suitable for use in this invention are those known in the art, which include, but are not limited to, sildenafil, tadalafi and vardenafil. In one preferred example, the PDE-5 inhibitor is vardenafil.
• the enhancer suitable for use in this invention includes, but is not limited to, cocamidopropyl betaine, sodium lauroamphoacetate, quaternium-60, isostearamidopropyl morpholine lactate, dipropylene glycol and a combination thereof.
• Cocamidopropyl betaine or ⁇ [3-(Dodecanoylamino)propyl](dimethyl)ammonio ⁇ acetate is a synthetic surfactant derived from coconut oil and dimethylaminopropylamine.
• 2-[l-(2-hydroxyethyl)-2-undecyl-4,5-dihydroimidazol-l-ium-l-yl]acetate is an amphoacetate commonly used in moisturizers.
• Quaternium-60 is an active quaternary commonly dissolved in propylene glycol.
• the PDE-5 inhibitor and the enhancer are present in a ratio from about 20:1 to 2:1, preferably about 5:1 in the improved composition.
• the PDE-5and the enhancer are present in the improved composition in a ratio of about 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1. 4:1, 3:1 or 2:1.
• the PDE-5 inhibitor is vardenafil, and the enhancer is cocamidopropyl betaine; and the PDE-5 inhibitor and the enhancer are present in a ratio of about 5:1 in the improved composition.
• the PDE-5 inhibitor is vardenafil, and the enhancer is a one-to-one mixture of cocamidopropyl betaine and sodium lauroamphoacetate; and the PDE-5 inhibitor and the enhancer are present in a ratio of about 6:1 in the improved composition.
• the PDE-5 inhibitor is vardenafil, and the enhancer is a mixture of cocamidopropyl betaine, sodium lauroamphoacetate and quaternium-60; and the PDE-5 inhibitor and the enhancer are present in a ratio of about 4:1 in the improved composition.
• the PDE-5 inhibitor is vardenafil
• the enhancer is a mixture of cocamidopropyl betaine, sodium lauroamphoacetate, quaternium-60, isostearamidopropyl morpholine lactate, and dipropyfene glycol; and the PDE-5 inhibitor and the enhancer are present in a ratio of about 3:1 in the improved composition.
• compositions of this invention may be formulated into a variety of dosage forms for topical application.
• a wide variety of dermatologically acceptable inert excipients well known to the art may be employed.
• the topical compositions may include liquids, pastes, creams, lotions, ointments, gels, sprays, aerosols, skin patches, and the like.
• Typical inert excipients may be, for example, water, ethyl alcohol, polyvinyl pyrrolidone, propylene glycol, mineral oil, stearyl alcohol and gel-producing substances. All of the above dosages forms and excipients are well known to the pharmaceutical art. The choice of the dosage form is not critical to the efficacy of the composition described herein.
• the improved composition can include volatile carriers such as ethanol and water as well as non-volatile carriers such as medium chain length triglyceride and straight chain aliphatic alcohols.
• volatile carriers such as ethanol and water
• non-volatile carriers such as medium chain length triglyceride and straight chain aliphatic alcohols.
• a typical solution composition of this invention includes at least, a concentration of the PDE-5 inhibitor in a range of about 1-20% by weight, a concentration of the enhancer in a range of about 0.2-5% by weight, and a concentration of volatile and non-volatile carriers in the range of about 0.5-98% by weight, respectively.
• the improved composition can include a finely divided solid and a thickener.
• a typical lotion composition of this invention includes at least, a concentration of the PDE-5 inhibitor in a range of about 1-20% by weight, a concentration of the enhancer in a range of about 0.2-5% by weight, a concentration of the finely divided solid in the range of about 0.5-5% by weight, and a concentration of the thickener in the range of about 2-5% by weight.
• the improved composition can include emollient and an emulsifier, as well as an antioxidant and/or preservative.
• a typical cream composition of this invention includes at least, a concentration of the PDE-5 inhibitor in a range of about 1-20% by weight, a concentration of the enhancer in a range of about 0.2-5% by weight, a concentration of the emollient in the range of about 0-50% by weight, and a concentration of the emulsifier in the range of about 0-20% by weight.
• the improved composition can include a gelling agent such as a finely divided solid and/or thickener in concentrations that produce a loose molecular network inhibiting the free movement of liquid ingredients.
• a gelling agent such as a finely divided solid and/or thickener in concentrations that produce a loose molecular network inhibiting the free movement of liquid ingredients.
• a typical gel composition of this invention includes at least, a concentration of the
• PDE-5 inhibitor in a range of about 1-20% by weight, a concentration of the enhancer in a range of about 0.2-5% by weight, a concentration of the thickener in the range of about 2-5% by weigh, and a concentration of the finely divided solid in the range of about 0-20% by weight.
• compositions of this invention may also be formulated into an aerosol formulation for drug delivery through skin.
• a typical aerosol composition of this invention includes, at least, a concentration of the PDE-5 inhibitor in a range of about 1-20% by weight, a concentration of the enhancer in a range of about 0.2-5% by weight, a concentration of a propellant and/or co-solvent in a range of 10-90% by weight.
• Suitable propellants and/or co-solvents for solubilizing the PDE-5 inhibitor and the enhancer of this invention in medicinal aerosol formulations are well known in this art.
• Typical propellants are hydrofluoroalkanes such as 1,1,1,2-tetrafluoroethane (HFA-134a), 1,1,1,2,3,3,3-heptafluoropropane (HFA-227ea). pentafluoroethane (HFA-125),
• HFA-152a 1,1-difluoroethane
• HFA-32 difluoromethane
• Typical co-solvents include, but not limited to, alcohols, polyols, alkoxy derivatives, fatty acid alkyl esters, polyalkylene glycols, dimethylsulphoxide and the like.
• the improved composition is administered to the recipient by means of a skin patch.
• the skin patch is prepared by incorporating in a matrix such as a gauze pad the improved formulation of this invention (e.g., any of the gel formulations 2 to 5 of Example 2.1).
• Transdermal delivery is accomplished by exposing the recipient's skin to one side of the patch for an extended period of time, so that PDE-5 inhibitor is released on to and across the recipient's skin.
• Many suitable transdermal delivery patches are known, ranging from a simple gauze pad impregnated with the formulation of this invention and secured to the skin with an adhesive bandage to multilayer structures.
• a transdermal delivery patch may also contain other added substances that enhance the penetration of the PDE-5 inhibitor, i.e., substances other than the enhancer identified by the inventors of this application.
• substances other than the enhancer identified by the inventors of this application i.e., substances other than the enhancer identified by the inventors of this application.
• Many known enhancers may be used together with the enhancers of this invention, to improve skin penetration of PDE-5 inhibitor.
• the improved composition of this invention can be prepared by conventional procedures, such as those described in Remington's Pharmaceutical Sciences, 17 th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa (1985).
• Pharmaceutically acceptable excipients are those that are compatible with other ingredients in the formulation and biologically acceptable.
• sterilized equipment is preferably used.
• the composition can be packaged and stored in any suitable container inert to the contents including aluminum, glass, stainless steel, and solvent resistant plastics including polyamide, polyester, polypropylene, and ABS polymer. Storage is preferably in a cool place away from strong sunlight. Continued sterility can be assured by conventional techniques including aseptic packaging and post-sterilization in the final package by electron beam exposure.
• this invention also provides methods of treating mammals, preferably humans, for conditions or diseases mediated by PDE-5, such as erectile dysfunction or primary pulmonary hypertension.
• the method comprises the step of administrating the improved pharmaceutical composition of this invention to the mammals in need thereof. Accordingly, such composition is transdermally administered to a mammal, preferably human, with an enhanced absorption of the PDE-5 inhibitor by the human subject.
• the permeation test was carried out using in vitro Franz diffusion cell with a diffusion area of 0.785 cm 2 .
• a piece of rat (Sprague-Dawley) skin tissue was mounted between the two half-cells and fastened with a clamp.
• Aliquots of 1% (wt%) vardenafil with or without the addition of the enhancer of this disclosure, such as 0.3% (wt%) cocamidopropyl betaine, 1% (wt%) sodium lauroamphoacetate, 1% (wt%) isostearamidopropyl morpholine lactate, 1% (wt%) quaternium-60 or dipropyl glycol were applied to the Donor compartment to start the experiment.
• the receiver compartment was filled with PBS and the temperature was held at 37°C . Samples were taken at certain time intervals and assayed by HPLC. Amounts of vardenafil accumulated in the receiver compartment were calculated and results were summarized in FIG 1, wherein :
• Formulations (# 1 to 4) were prepared by stirring together separately prepared pre-mixtures of water insoluble ingredients and the water-soluble ingredients as tabulated bellow (all quantities are in weight %) until gels were formed, then adjusted the pH of the respective gel formulations to a range between 2.5 and 3.5.
• Formulation (#5) was prepared using ingredients tabulated bellowed (all ingredients were listed in weight %) in accordance with similar procedure as described above in example 2.1. The thus obtained formulation (# 5) was then applied onto the surface of a non-woven cloth, and let stand for 7 days until it gelled, thereby forming the desired skin patch. [0017]
• the enhancer(s) identified in the present invention when applied simultaneously with vardenafil, either alone or in combination, significantly enhances the permeation of vardenafil across the skin, with the amount of vardenafil found in the blood stream increased by about 4 to 5 folds, as compared with that of the control.

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• 2011
  • 2011-12-26 HU HUE11878502A patent/HUE041292T2/hu unknown
  • 2011-12-26 WO PCT/CN2011/084647 patent/WO2013097074A1/en active Application Filing
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  • 2011-12-26 CN CN201180073107.3A patent/CN103998043B/zh active Active
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• 2012
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• 2016
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